What are mTORC1 and Rapamycin and How do They Extend Longevity?
Lessons from David Sabatini — the world’s expert on mTOR
Your body is the craziest piece of technology you own. More than the Internet that connects the world, the transistors that power phones and computers, or artificial intelligence embedded in the products we use.
Recently, I have been really interested in the molecular biology of our body and how it changes as we age. Only after researching this topic have I gained a true appreciation for how complex and numerous the biological pathways that comprise our body are.
Even though our body as a whole is more powerful/complex than the average computer, a computer makes a very nice analogy to our body. The cells and all the different organelles are like the hardware of our bodies. The biological pathways that transmit signals from organelle to organelle are the software of our body.
Understanding the software of our bodies is key to understanding problems that go back to my motivation: the aging process. One key node that affects several biological pathways all relevant to aging is called mTORC1. mTORC1 and the molecule that inhibits it — rapamycin — have received a lot of attention from the longevity community and I have spent the past week trying to understand its importance to the function of our cell and why altering it has such a large effect on lifespan.
Discovery of mTORC1 and Rapamycin ?
Rapamycin was first discovered in a soil sample in 1972 on Easter Island, colloquially known as Rapa Nui which is where the name rapamycin comes from. At the time researchers could test what rapamycin did — they found it was a useful immunosuppressant — but they did not know what it’s protein target was.
Decades later in a lab at Johns Hopkins work took place to learn what the protein target of rapamycin was. The work of David Sabatini who was a graduate student discovered and sequenced the target — a protein known as mTOR (mammalian target of rapamycin). More info on how he discovered mTOR can be found in his lecture on mTOR if you are curious.
An important thing they learned about mTOR is that it was a kinase. A kinase is a protein that phosphorylates (adds a phosphate group) to an amino acid. This is important because the phosphate group basically acts as a flag telling other proteins to bind on top of the phosphate.
What they later found is that mTOR is part of a protein complex called mTORC1. A protein complex is simply a group of proteins that are linked (non-covalently) to perform a common function.
Functions of mTORC1
mTORC1 is what connects my introduction of all the different biological pathways. mTORC1 is one of the most important protein complexes in our body because it is a connecting factor of many biological pathways in our body. The main function of mTORC1 is the regulation of growth.
This is very important so I think it is necessary to repeat. The main function of mTORC1 is the regulation of growth.
Information that mTORC1 takes in (Also known as upstream effects):
- nutrients in the form of amino acids (leucine, arginine, and lysine specifically)
- growth factors/hormones like insulin. (other cells in the body telling the cell to grow)
- energy levels — ATP.
- DNA damage (p53) can inhibit mTORC1
At a high level, mTORC1 takes in all of this information from the cell through different binding sites in the complex. With this information, it can make decisions on what functionalities to do.
Things that mTORC1 can do (Also known as downstream effects) :
- phosphorylate p70S6K which later effects pyrimidine synthesis (nucleotide synthesis), ribosome activation, polypeptide translation, and synthesis in the ribosome. All of the ribosomal effects positively impact protein synthesis which is important for growth.
- inhibits ULK1 which inhibits autophagy. Autophagy is the process where things are degraded in the cell. If you are trying to grow then you do not want this to happen.
- inhibits TFEB which is a transcription factor for lysosomes the organelles that carry out autophagy. This also effectively inhibits autophagy.
- inhibits Erk5 which inhibits proteasomal degradation.
All of the functions of mTORC1 promote growth. In fact,mTORC1 is known as the “master regulator of growth” because it is able to take input from so many different places and affect growth in many different ways. mTORC1 can sense when nutrients fluctuate and if they go down to a certain extent it can stop growth activating, what David Sinclair calls, the “survival circuit”.
Problems with mTORC1 As We Age
As we age, there are problems with the signaling of nutrients by mTORC1. What seems to happen is that mTORC1 stays perpetually on and continues to activate growth even when the cell does not have sufficient nutrients. The mechanisms behind this are still unclear and I am doing further research as to why this occurs.
If we go back to our computer analogy, you can think of mTORC1 as a logic gate to the computer of our body. It takes in all of the inputs and if they are all-sufficient it will turn on. What seems to be occurring, is that in our old cells the mTORC1 as an OR logic gate. If some of the processes to activate growth are necessary then it will be activated. In reality, it should be acting like a AND logic gate where both all of the inputs should be correct.
Another main idea here is to basically take mTORC1 activity and reduce it to an optimal level. As you can see in the graph above the level of mTORC1 activity increase with problems like obesity/high-fat diet which promotes growth. Lifestyles like caloric restriction, which is closer to what evolutionarily are bodies were primed for, are closer to the global maxima of health.
By supplementing molecules like rapamycin we are trying to reduce the activity of mTORC1 to get close to that global maxima.
Rapamycin’s effect on mTORC1
Rapamycin inhibits mTORC1 — inhibiting the growth of the cell. This has a positive effect because it reverts the cell back to a proper condition of not growing and taking up resources instead of “hunkering down to survive”. This mechanism extends longevity. Also by inhibiting mTORC1, more autophagy happens so more waste of the cell is flushed away which is a good effect.
Through different peer-reviewed studies, it has been shown that rapamycin increases lifespan in mammalian model organisms up to 110%. Here is a link to a review article that cites some of the recent studies that have been done. This resource on Laura Deming’s (a prominent longevity investor) website has a list of companies working on developing rapamycin the drug as well as other small molecules that act like rapamycin called rapalogs.
A big company that was working on the TORC1 pathway was resTORbio but actually today they merged with Adicet Bio to focus on Car T Cell Therapy.
- mTORC1 is one of the most important nodes of our biological pathways because it plays a big part in regulating growth.
- Rapamycin can inhibit mTORC1 and increase lifespan as shown in Animal models.